In the last years, intensive research for therapeutics with activity against infection by HIV was performed. Several medicaments were developed and tested, which delay and suppress the outbreak of AIDS and lower the level of the HIV in blood. In the US the life-span of HIV-infected patients after the outbreak of AIDS was raised from 11 month in 1984 to 46 month in 1997. In the search for therapeutics various strategies were applied, which lead to several classes of medicaments such as the protease-blockers inhibiting a protease, which the virus requires for replication, and medicaments inhibiting the viral reverse transcriptase, which is essential for the replication of retroviruses. A group of active agents developed only recently are fusion inhibitors, which shall prevent the entry of the virus into cells. It was also shown that the provision of interleukin-2 in combination with other active agents could increase the strength of the immune response.
Entry inhibitors block the uptake of HIV viral particles into blood cells by blocking one of the molecular steps occurring during viral entry. An important step is binding of HIV to one of the major chemokine coreceptors CCR5 and CXCR4 (CC chemokine receptor 5 and CXCR chemokine receptor 4). These coreceptors are located on the surface of blood cells and are required to bind to HIV envelope proteins before viral entry. Another step of viral interaction with cells required for fusion is the binding of the HIV envelope protein gp120 to cellular CD4 receptors. These steps are often referred to as attachment of the viral particle to cellular targets. The blocking of the binding of HIV to chemokine coreceptors has been shown to suppress viral entry (Strizki J. M., Proc. Natl. Acad. Sci. USA, 2001, 98, 12718-12723). The same was reported by blocking the interaction of gp120 with CD4 receptors (Lin et al., Proc. Natl. Acad. Sci. USA, 2003, 100, 11013-11018). The HIV protein gp41 has also been recognised as a potential target for anti-HIV drug development (Gordon et al., AIDS Research and Human Retroviruses 11, 677-686, 1995). The first approved fusion inhibitor is enfuvirtide (T-20, Fuzeon, DP178) (WO 01/51673 A2; WO 96/40191; Cervia J. S. et al., Clin. Infect. Dis, 2003, 37, 1102-1106; Kilby J. M., Nature Medicine, 1998, 4, 1302-1307). This fusion inhibitor is identical to a part of the HIV envelope protein gp41 called HR-2 and inhibits HIV-cell fusion by binding to the HR-1 segment (HR=heptad repeat) of gp41 (FIG. 4), thus preventing the binding of HR-2 to the HR-1 segment of gp41 which in turn prevents the formation of a six-helix bundle required for fusion of the viral particle and the blood cell. T-20 has not been shown to bind to protein segments other than HR-1 of HIV gp41 or even other molecules of viral or eukaryotic origin. A further agent with biological activity against HIV was recently described in WO 01/34640. Disclosed is a peptide of 20 amino acids named VIRIP (virus inhibiting peptide), which was isolated from human hemofiltrate and found to inhibit the infection of human cells by HIV.
Despite those efforts and different available medication, the problem remains unsolved that there is still no cure against AIDS, because the known therapeutics, though capable of significantly lowering the level of HIV in the body and of HIV-infected blood cells, do not remove the virus entirely. A special drawback is, that the HIV is especially prone to mutations, which often result in the development of resistance against certain therapeutics. In general, the known therapeutics are only sufficiently effective if they are administered in combination with other therapeutics. Such combined therapies at present extend the lifespan of the average patient without providing a cure, and are generally accompanied by severe side effects and frequently do not allow the patient to lead a “normal” life.
There is a great medical need to provide new therapeutics and improved therapeutics, which will lead to improved therapies, less side effects, and significant extension of the life expectancy of those infected by HIV, before or after the outbreak of AIDS.
The present invention faces the problem to provide new therapeutics, which will overcome the problems as described above, and will allow an efficient therapy or will contribute to an efficient combination therapy.